HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Adeno-associated viral-mediated LARGE gene therapy rescues the muscular dystrophic phenotype in mouse models of dystroglycanopathy.

Abstract
Dystroglycanopathies are a group of congenital muscular dystrophies (CMD) often caused by mutations in genes encoding glycosyltransferases that lead to hypoglycosylation of α-dystroglycan (α-DG) and reduce its extracellular matrix-binding activity. Overexpressing LARGE (formerly known as like-glycosyltransferase) generates an extracellular matrix-binding carbohydrate epitope in cells with CMD-causing mutations in not only LARGE but also other glycosyltransferases, including POMT1, POMGnT1, and fukutin, creating the possibilities of a one-for-all gene therapy. To determine the feasibility of LARGE gene therapy, a serotype 9 adeno-associated viral vector for overexpressing LARGE (AAV9-LARGE) was injected intracardially into newborns of two mouse models of CMD: the natural LARGE mutant Large(myd) mice and protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice. AAV9-LARGE virus treatment yielded partial restoration of α-DG glycosylation and ligand-binding activity. The muscular dystrophy phenotype in skeletal muscles was ameliorated as revealed by significantly reduced fibrosis, necrosis, and numbers of centrally located nuclei with improved motor function. These results indicate that LARGE overexpression in vivo by AAV9-mediated gene therapy is effective at restoring functional glycosylation of α-DG and rescuing the muscular dystrophy phenotype in deficiency of not only LARGE but also POMGnT1, providing evidence that in vivo LARGE gene therapy may be broadly useful in dystroglycanopathies.
AuthorsMiao Yu, Yonglin He, Kejian Wang, Peng Zhang, Shengle Zhang, Huaiyu Hu
JournalHuman gene therapy (Hum Gene Ther) Vol. 24 Issue 3 Pg. 317-30 (Mar 2013) ISSN: 1557-7422 [Electronic] United States
PMID23379513 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Dystroglycans
  • Large1 protein, mouse
  • N-Acetylglucosaminyltransferases
Topics
  • Animals
  • Dependovirus (genetics)
  • Disease Models, Animal
  • Dystroglycans (metabolism)
  • Fibrosis (genetics, prevention & control)
  • Genetic Therapy
  • Genetic Vectors (administration & dosage, genetics)
  • Glycosylation
  • Mice
  • Mice, Transgenic
  • Motor Activity
  • Muscle, Skeletal (metabolism, pathology)
  • Muscular Dystrophies (genetics, therapy)
  • N-Acetylglucosaminyltransferases (genetics)
  • Phenotype
  • Transduction, Genetic

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: